The present invention relates to a method of stably preserving a quaternary ammonium salt that is favorably used as a condensing agent for the preparation of amide compounds and ester compounds, to a method of preparing a stabilized quaternary ammonium salt, to a condensing agent using the stabilized quaternary ammonium salt as an effective component, and to a method of preparing amide compounds or ester compounds using the above condensing agent.
Amide compounds and ester compounds are very important compounds for forming basic skeletons of a variety of organic compounds such as medicines, agricultural chemicals, dyes and high-molecular compounds. Therefore, study has long been conducted concerning the method of preparing amide compounds and ester compounds. As methods of preparing amide compounds, for example, there have generally been known a method of preparing amide compounds by an exchange reaction of an ester compound with an amine compound, and a method of directly preparing amide compounds from a carboxylic acid compound and an amine compound. As the methods of preparing ester compounds, further, there have generally been known a method of directly preparing ester compounds from a carboxylic acid and an alcohol compound in the presence of an acid, and a method of preparing ester compounds by forming a carboxylic acid chloride by the reaction of a carboxylic acid compound with an acid-halogenating agent such as thionyl chloride, followed by being acted with an alcohol.
However, the method of preparing amide compounds is conducted under a heated condition, and cannot be conducted for preparing the compounds which are not thermally stable or for preparing compounds having both an amino group and an alkoxycarbonyl group in the same molecule. Further, the method of preparing ester compounds is conducted under an acidic condition, and cannot be conducted for preparing compounds which are not stable against acids.
In order to solve the above problems, there have been proposed various methods using a condensing agent such as a carbodiimide in order to prepare amide compounds under mild conditions. In particular, a 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride proposed as a condensing agent for the synthesis of amide compounds by Z. J. Kaminski et al. {Journal of Organic Chemistry, Vol. 63, pp. 4248-4255, 1998} is drawing attention since it does not cause eruption that is caused by the carbodiimide-type condensing agent.
As for the preparation of ester compounds, further, a method of preparing ester compounds under mild conditions has been proposed by Mukaiyama et al by using a condensing agent comprising a pyridinium oxide compound {Bulletin of Chemical Society of Japan, Vol. 50, pp. 1863-1866, 1977}.
According to the method proposed by Kaminski et al. disclosed in the above literature, however, a carboxylic acid compound and a condensing agent are reacted together each in an amount of an equal mol to once form a reactive derivative which is an intermediate product and, then, the reactive derivative is reacted with an amine compound to obtain an amide compound. Therefore, the yield varies as widely as from 17 to 73%, which is far from satisfactory.
In preparing the above pyridinium oxide compound that is used for the preparation of ester compounds, further, it is necessary to use a methyl iodide which has been pointed out to be carcinogenic. Therefore, careful attention must be paid concerning the working environment.
In order to solve such problems, the present inventors have forwarded the study and have discovered that when a condensing agent comprising a quaternary ammonium salt represented by the following general formula (I),                 wherein R1 is an alkyl group having 1 to 4 carbon atoms or an aryl group having 6 to 8 carbon atoms, R2 is an alkyl group having 1 to 4 carbon atoms, and X is a halogen atom,a carboxylic acid compound and an amine compound are mixed and reacted together but without conducting the above-mentioned two-step reaction, then, the yield is improved, the reaction time is shortened and, besides, the condensing agent forms an amide compound in a high yield in a protonic organic solvent unlike the carbodiimide-type condensing agent which is the most widely used condensing agent (Japanese Patent Application No. 60765/1999, PCT/JP00/00834).        
As for preparing the ester compounds, the inventors have discovered that the ester compounds can be prepared under mild conditions when a carboxylic acid compound is reacted with an alcohol compound by using the same condensing agent as the one used for the above-mentioned method of preparing the amide compounds proposed by the present inventors (Japanese Patent Application No. 137693/1999, PCT/JP00/00834).
While forwarding the study concerning the condensation reaction by using a quaternary ammonium salt represented by the above-mentioned general formula (I), however, the present inventors have noticed that the quaternary ammonium salt involves a problem concerning the stability. Namely, it became obvious that the quaternary ammonium salt undergoes the decomposition reaction during the preparation, preservation or use thereof. This means that the quaternary ammonium salt not only loses its purity and yield of condensation but also requires attention concerning its preservation and handling.
Usually, further, the quaternary ammonium salt represented by the above-mentioned general formula (I) can be prepared by reacting a triazine compound and a morpholine compound of corresponding structures together in an organic solvent. With this method, however, the reaction is not completed even after the passage of a long period of time and, as a result, the quaternary ammonium salt prepared by this method contains unreacted triazine compound in an amount of from about 1 to about 5%.